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COVID-19 and Molecular Studies in Biology and Chemistry

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 90117

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Special Issue Editors

Prof. Dr. Cristina Belizna

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Guest Editor

Vascular and Coagulation Department, University Hospital Angers, 49100 Angers, France
Interests: antiphospholipid syndrome; OMICS; immune; autoimmune; rheumatology
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Jan Willem Cohen Tervaert

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Guest Editor

Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
Interests: immunology of rheumatic disorders and COVID-19; vascular immunology; pathophysiology of vasculitis and atherosclerosis; auto-immunity to myeloïd lysosomal enzymes (ANCA); pathophysiology of foreign-body induced autoimmunity; ASIA (Shoenfeld's) syndrome; role of vitamin D in auto-immune diseases
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Yehuda Shoenfeld

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1. Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Ramat Gan 52621, Israel
2. Laboratory of the Mosaics of Autoimmunity, Saint Petersburg State University, 199034 Saint-Petersburg, Russia
Interests: clinical immunology; autoimmune diseases; rheumatology diseases; lupus
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Alexander Makatsariya

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Vice-President of Russian Society of Obstetricians and Gynecologists, Academician of the Russian Academy of Sciences,The First I.M. Sechenov Moscow State Medical University, Moscow, Russia
Interests: thrombosis; thromboinflammation; disseminated intravascular coagulation syndrome; systemic inflammatory response syndrome; preeclampsia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We kindly invite to send your results and idea for a special issue on the topic on COVID 19 and molecular studies in biology and chemistry, as we strongly believe that only a brainstorming in this field would allow a fast and reliable avance in understanding of this major threat of the humanity, analyze and build solutions together, and to go further to treatment and vaccines trials.

Scope of the special issue

As only international multidisciplinary information, both fast and reliable, would allow to medical world to face COVID-19 pandemia, we want to focuss a special issue on molecular studies in biology and chemistry, to avance together with researchers for the understanding of this major threat of the humanity, analyze and build solutions, and to go further to treatment and vaccines trials.

Prof. Dr. Cristina Belizna
Prof. Jan Willem Cohen Tervaert
Prof. Yehuda Shoenfeld
Prof. Alexander Makatsariya
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

COVID-19
Genetics
Epigenetics
Biomolecular sciences
Environmental sciences
Fundamental chemical sciences

Published Papers (13 papers)

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Research

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17 pages, 13957 KiB

Open AccessArticle

Computational Selectivity Assessment of Protease Inhibitors against SARS-CoV-2

by André Fischer, Manuel Sellner, Karolina Mitusińska, Maria Bzówka, Markus A. Lill, Artur Góra and Martin Smieško

Int. J. Mol. Sci. 2021, 22(4), 2065; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042065 - 19 Feb 2021

Cited by 5 | Viewed by 3978

Abstract

The pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious global health threat. Since no specific therapeutics are available, researchers around the world screened compounds to inhibit various molecular targets of SARS-CoV-2 including its main protease (M^pro) essential for viral replication. Due to the high urgency of these discovery efforts, off-target binding, which is one of the major reasons for drug-induced toxicity and safety-related drug attrition, was neglected. Here, we used molecular docking, toxicity profiling, and multiple molecular dynamics (MD) protocols to assess the selectivity of 33 reported non-covalent inhibitors of SARS-CoV-2 M^pro against eight proteases and 16 anti-targets. The panel of proteases included SARS-CoV M^pro, cathepsin G, caspase-3, ubiquitin carboxy-terminal hydrolase L1 (UCHL1), thrombin, factor Xa, chymase, and prostasin. Several of the assessed compounds presented considerable off-target binding towards the panel of proteases, as well as the selected anti-targets. Our results further suggest a high risk of off-target binding to chymase and cathepsin G. Thus, in future discovery projects, experimental selectivity assessment should be directed toward these proteases. A systematic selectivity assessment of SARS-CoV-2 M^pro inhibitors, as we report it, was not previously conducted. Full article

(This article belongs to the Special Issue COVID-19 and Molecular Studies in Biology and Chemistry)

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13 pages, 2775 KiB

Open AccessArticle

Human Milk Antibodies against S1 and S2 Subunits from SARS-CoV-2, HCoV-OC43, and HCoV-229E in Mothers with a Confirmed COVID-19 PCR, Viral SYMPTOMS, and Unexposed Mothers

by Veronique Demers-Mathieu, Ciera DaPra, Gabrielle Mathijssen, David A. Sela, Kirsi M. Järvinen, Antti Seppo, Shawn Fels and Elena Medo

Int. J. Mol. Sci. 2021, 22(4), 1749; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041749 - 09 Feb 2021

Cited by 27 | Viewed by 4907

Abstract

Background: Preexisting immunity to SARS-CoV-2 could be related to cross-reactive antibodies to common human-coronaviruses (HCoVs). This study aimed to evaluate whether human milk antibodies against to S1 and S2 subunits SARS-CoV-2 are cross-reactive to S1 and S2 subunits HCoV-OC43 and HCoV-229E in mothers with a confirmed COVID-19 PCR test, in mothers with previous viral symptoms during COVID-19 pandemic, and in unexposed mothers; Methods: The levels of secretory IgA (SIgA)/IgA, secretory IgM (SIgM)/IgM, and IgG specific to S1 and S2 SARS-CoV-2, and reactive to S1 + S2 HCoV-OC43, and HCoV-229E were measured in milk from 7 mothers with a confirmed COVID-19 PCR test, 20 mothers with viral symptoms, and unexposed mothers (6 Ctl1-2018 and 16 Ctl2-2018) using ELISA; Results: The S2 SARS-CoV-2 IgG levels were higher in the COVID-19 PCR (p = 0.014) and viral symptom (p = 0.040) groups than in the Ctl1-2018 group. We detected a higher number of positive correlations between the antigens and secretory antibodies in the COVID-19 PCR group than in the viral symptom and Ctl-2018 groups. S1 + S2 HCoV-OC43-reactive IgG was higher in the COVID-19 group than in the control group (p = 0.002) but did not differ for the other antibodies; Conclusions: Mothers with a confirmed COVID-19 PCR and mothers with previous viral symptoms had preexisting human milk antibodies against S2 subunit SARS-CoV-2. Human milk IgG were more specific to S2 subunit SARS-CoV-2 than other antibodies, whereas SIgA and SIgM were polyreactive and cross-reactive to S1 or S2 subunit SARS-CoV-2. Full article

(This article belongs to the Special Issue COVID-19 and Molecular Studies in Biology and Chemistry)

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15 pages, 2144 KiB

Open AccessArticle

Establishment of Murine Hybridoma Cells Producing Antibodies against Spike Protein of SARS-CoV-2

by Nadezhda V. Antipova, Tatyana D. Larionova, Andrei E. Siniavin, Maria A. Nikiforova, Vladimir A. Gushchin, Igor I. Babichenko, Alexey V. Volkov, Michail I. Shakhparonov and Marat S. Pavlyukov

Int. J. Mol. Sci. 2020, 21(23), 9167; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239167 - 01 Dec 2020

Cited by 7 | Viewed by 3884

Abstract

In 2020 the world faced the pandemic of COVID-19 severe acute respiratory syndrome caused by a new type of coronavirus named SARS-CoV-2. To stop the spread of the disease, it is crucial to create molecular tools allowing the investigation, diagnoses and treatment of COVID-19. One of such tools are monoclonal antibodies (mAbs). In this study we describe the development of hybridoma cells that can produce mouse mAbs against receptor binding domain of SARS-CoV-2 spike (S) protein. These mAbs are able to specifically detect native and denatured S proteins in all tested applications, including immunoblotting, enzyme-linked immunosorbent assay, immunofluorescence staining of cells and immunohistochemical staining of paraffin embedded patients’ tissue samples. In addition, we showed that the obtained mAbs can efficiently block SARS-CoV-2 infection in in vitro experiments. Finally, we determined the amino acid sequence of light and heavy chains of the mAbs. This information will allow the use of corresponding peptides to establish genetically engineered therapeutic antibodies. To date multiple mAbs against SARS-CoV-2 proteins have been established, however, bigger sets of various antibodies will allow the detection and neutralization of SARS-CoV-2, even if the virus acquires novel mutations. Full article

(This article belongs to the Special Issue COVID-19 and Molecular Studies in Biology and Chemistry)

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15 pages, 2228 KiB

Open AccessArticle

Immune-Modulating Drug MP1032 with SARS-CoV-2 Antiviral Activity In Vitro: A potential Multi-Target Approach for Prevention and Early Intervention Treatment of COVID-19

by Sara Schumann, Astrid Kaiser, Ferdinando Nicoletti, Katia Mangano, Paolo Fagone, Eduard van Wijk, Yu Yan, Petra Schulz, Beate Ludescher, Michael Niedermaier, Joerg von Wegerer, Pia Rauch, Christian Setz, Ulrich Schubert and Wolfgang Brysch

Int. J. Mol. Sci. 2020, 21(22), 8803; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228803 - 20 Nov 2020

Cited by 7 | Viewed by 3558

Abstract

At least since March 2020, the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic and the multi-organ coronavirus disease 2019 (COVID-19) are keeping a firm grip on the world. Although most cases are mild, older patients and those with co-morbidities are at increased risk of developing a cytokine storm, characterized by a systemic inflammatory response leading to acute respiratory distress syndrome and organ failure. The present paper focuses on the small molecule MP1032, describes its mode of action, and gives rationale why it is a promising option for the prevention/treatment of the SARS-CoV-2-induced cytokine storm. MP1032 is a phase-pure anhydrous polymorph of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt that exhibits good stability and bioavailability. The physiological action of MP1032 is based on a multi-target mechanism including localized, self-limiting reactive oxygen species (ROS) scavenging activities that were demonstrated in a model of lipopolysaccharide (LPS)-induced joint inflammation. Furthermore, its immune-regulatory and PARP-1-modulating properties, coupled with antiviral effects against SARS-CoV-2, have been demonstrated in various cell models. Preclinical efficacy was elucidated in LPS-induced endotoxemia, a model with heightened innate immune responses that shares many similarities to COVID-19. So far, during oral clinical development with three-month daily administrations, no serious adverse drug reactions occurred, highlighting the outstanding safety profile of MP1032. Full article

(This article belongs to the Special Issue COVID-19 and Molecular Studies in Biology and Chemistry)

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25 pages, 4673 KiB

Open AccessArticle

Large-Scale Plasma Analysis Revealed New Mechanisms and Molecules Associated with the Host Response to SARS-CoV-2

by Elettra Barberis, Sara Timo, Elia Amede, Virginia V. Vanella, Chiara Puricelli, Giuseppe Cappellano, Davide Raineri, Micol G. Cittone, Eleonora Rizzi, Anita R. Pedrinelli, Veronica Vassia, Francesco G. Casciaro, Simona Priora, Ilaria Nerici, Alessandra Galbiati, Eyal Hayden, Marco Falasca, Rosanna Vaschetto, Pier Paolo Sainaghi, Umberto Dianzani, Roberta Rolla, Annalisa Chiocchetti, Gianluca Baldanzi, Emilio Marengo and Marcello Manfredi Show full author list Hide full author list

Int. J. Mol. Sci. 2020, 21(22), 8623; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228623 - 16 Nov 2020

Cited by 161 | Viewed by 7687

Abstract

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to nearly every continent, registering over 1,250,000 deaths worldwide. The effects of SARS-CoV-2 on host targets remains largely limited, hampering our understanding of Coronavirus Disease 2019 (COVID-19) pathogenesis and the development of therapeutic strategies. The present study used a comprehensive untargeted metabolomic and lipidomic approach to capture the host response to SARS-CoV-2 infection. We found that several circulating lipids acted as potential biomarkers, such as phosphatidylcholine 14:0_22:6 (area under the curve (AUC) = 0.96), phosphatidylcholine 16:1_22:6 (AUC = 0.97), and phosphatidylethanolamine 18:1_20:4 (AUC = 0.94). Furthermore, triglycerides and free fatty acids, especially arachidonic acid (AUC = 0.99) and oleic acid (AUC = 0.98), were well correlated to the severity of the disease. An untargeted analysis of non-critical COVID-19 patients identified a strong alteration of lipids and a perturbation of phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, aminoacyl-tRNA degradation, arachidonic acid metabolism, and the tricarboxylic acid (TCA) cycle. The severity of the disease was characterized by the activation of gluconeogenesis and the metabolism of porphyrins, which play a crucial role in the progress of the infection. In addition, our study provided further evidence for considering phospholipase A2 (PLA2) activity as a potential key factor in the pathogenesis of COVID-19 and a possible therapeutic target. To date, the present study provides the largest untargeted metabolomics and lipidomics analysis of plasma from COVID-19 patients and control groups, identifying new mechanisms associated with the host response to COVID-19, potential plasma biomarkers, and therapeutic targets. Full article

(This article belongs to the Special Issue COVID-19 and Molecular Studies in Biology and Chemistry)

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16 pages, 5578 KiB

Open AccessArticle

Existence of SARS-CoV-2 Entry Molecules in the Oral Cavity

by Wakako Sakaguchi, Nobuhisa Kubota, Tomoko Shimizu, Juri Saruta, Shinya Fuchida, Akira Kawata, Yuko Yamamoto, Masahiro Sugimoto, Mayumi Yakeishi and Keiichi Tsukinoki

Int. J. Mol. Sci. 2020, 21(17), 6000; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176000 - 20 Aug 2020

Cited by 130 | Viewed by 9980

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor, angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), and furin, which promote entry of the virus into the host cell, have been identified as determinants of SARS-CoV-2 infection. Dorsal tongue and gingiva, saliva, and tongue coating samples were examined to determine the presence of these molecules in the oral cavity. Immunohistochemical analyses showed that ACE2 was expressed in the stratified squamous epithelium of the dorsal tongue and gingiva. TMPRSS2 was strongly expressed in stratified squamous epithelium in the keratinized surface layer and detected in the saliva and tongue coating samples via Western blot. Furin was localized mainly in the lower layer of stratified squamous epithelium and detected in the saliva but not tongue coating. ACE2, TMPRSS2, and furin mRNA expression was observed in taste bud-derived cultured cells, which was similar to the immunofluorescence observations. These data showed that essential molecules for SARS-CoV-2 infection were abundant in the oral cavity. However, the database analysis showed that saliva also contains many protease inhibitors. Therefore, although the oral cavity may be the entry route for SARS-CoV-2, other factors including protease inhibitors in the saliva that inhibit viral entry should be considered. Full article

(This article belongs to the Special Issue COVID-19 and Molecular Studies in Biology and Chemistry)

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12 pages, 1038 KiB

Open AccessCommunication

HLA-B*44 and C*01 Prevalence Correlates with Covid19 Spreading across Italy

by Pierpaolo Correale, Luciano Mutti, Francesca Pentimalli, Giovanni Baglio, Rita Emilena Saladino, Pierpaolo Sileri and Antonio Giordano

Int. J. Mol. Sci. 2020, 21(15), 5205; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155205 - 23 Jul 2020

Cited by 63 | Viewed by 10922

Abstract

The spread of COVID-19 is showing huge, unexplained, differences between northern and southern Italy. We hypothesized that the regional prevalence of specific class I human leukocyte antigen (HLA) alleles, which shape the anti-viral immune response, might partly underlie these differences. Through an ecological approach, we analyzed whether a set of HLA alleles (A, B, C), known to be involved in the immune response against infections, correlates with COVID-19 incidence. COVID-19 data were provided by the National Civil Protection Department, whereas HLA allele prevalence was retrieved through the Italian Bone-Marrow Donors Registry. Among all the alleles, HLA-A*25, B*08, B*44, B*15:01, B*51, C*01, and C*03 showed a positive log-linear correlation with COVID-19 incidence rate fixed on 9 April 2020 in proximity of the national outbreak peak (Pearson’s coefficients between 0.50 and 0.70, p-value < 0.0001), whereas HLA-B*14, B*18, and B*49 showed an inverse log-linear correlation (Pearson’s coefficients between −0.47 and −0.59, p-value < 0.0001). When alleles were examined simultaneously using a multiple regression model to control for confounding factors, HLA-B*44 and C*01 were still positively and independently associated with COVID-19: a growth rate of 16% (95%CI: 0.1–35%) per 1% point increase in B*44 prevalence; and of 19% (95%CI: 1–41%) per 1% point increase in C*01 prevalence. Our epidemiologic analysis, despite the limits of the ecological approach, is strongly suggestive of a permissive role of HLA-C*01 and B*44 towards SARS-CoV-2 infection, which warrants further investigation in case-control studies. This study opens a new potential avenue for the identification of sub-populations at risk, which could provide Health Services with a tool to define more targeted clinical management strategies and priorities in vaccination campaigns. Full article

(This article belongs to the Special Issue COVID-19 and Molecular Studies in Biology and Chemistry)

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18 pages, 995 KiB

Open AccessReview

Does Genetic Predisposition Contribute to the Exacerbation of COVID-19 Symptoms in Individuals with Comorbidities and Explain the Huge Mortality Disparity between the East and the West?

by Naoki Yamamoto, Rain Yamamoto, Yasuo Ariumi, Masashi Mizokami, Kunitada Shimotohno and Hiroshi Yoshikura

Int. J. Mol. Sci. 2021, 22(9), 5000; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22095000 - 08 May 2021

Cited by 17 | Viewed by 4196

Abstract

The elderly and patients with several comorbidities experience more severe cases of coronavirus disease 2019 (COVID-19) than healthy patients without underlying medical conditions. However, it is unclear why these people are prone to developing alveolar pneumonia, rapid exacerbations, and death. Therefore, we hypothesized that people with comorbidities may have a genetic predisposition that makes them more vulnerable to various factors; for example, they are likely to become more severely ill when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To test this hypothesis, we searched the literature extensively. Polymorphisms of genes, such as those that encode angiotensin-converting enzyme 1 (ACE1), have been associated with numerous comorbidities, such as cardiovascular disease, hypertension, diabetes, chronic kidney disease, and obesity, and there are potential mechanisms to explain these associations (e.g., DD-type carriers have greater ACE1 activity, and patients with a genetic alpha-1 anti-trypsin (AAT) deficiency lack control over inflammatory mediators). Since comorbidities are associated with chronic inflammation and are closely related to the renin–angiotensin–aldosterone system (RAAS), these individuals may already have a mild ACE1/ACE2 imbalance before viral infection, which increases their risk for developing severe cases of COVID-19. However, there is still much debate about the association between ACE1 D/I polymorphism and comorbidities. The best explanation for this discrepancy could be that the D allele and DD subtypes are associated with comorbidities, but the DD genotype alone does not have an exceptionally large effect. This is also expected since the ACE1 D/I polymorphism is only an intron marker. We also discuss how polymorphisms of AAT and other genes are involved in comorbidities and the severity of SARS-CoV-2 infection. Presumably, a combination of multiple genes and non-genetic factors is involved in the establishment of comorbidities and aggravation of COVID-19. Full article

(This article belongs to the Special Issue COVID-19 and Molecular Studies in Biology and Chemistry)

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16 pages, 368 KiB

Open AccessReview

Do COVID-19 Infections Result in a Different Form of Secondary Hemophagocytic Lymphohistiocytosis

by Raymond Chu, Charmaine van Eeden, Sneha Suresh, Wendy I. Sligl, Mohammed Osman and Jan Willem Cohen Tervaert

Int. J. Mol. Sci. 2021, 22(6), 2967; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062967 - 15 Mar 2021

Cited by 10 | Viewed by 3425

Abstract

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant morbidity and mortality across the world, with no current effective treatments available. Recent studies suggest the possibility of a cytokine storm associated with severe COVID-19, similar to the biochemical profile seen in hemophagocytic lymphohistiocytosis (HLH), raising the question of possible benefits that could be derived from targeted immunosuppression in severe COVID-19 patients. We reviewed the literature regarding the diagnosis and features of HLH, particularly secondary HLH, and aimed to identify gaps in the literature to truly clarify the existence of a COVID-19 associated HLH. Diagnostic criteria such as HScore or HLH-2004 may have suboptimal performance in identifying COVID-19 HLH-like presentations, and criteria such as soluble CD163, NK cell activity, or other novel biomarkers may be more useful in identifying this entity. Full article

(This article belongs to the Special Issue COVID-19 and Molecular Studies in Biology and Chemistry)

24 pages, 1530 KiB

Open AccessReview

Understanding Viral Infection Mechanisms and Patient Symptoms for the Development of COVID-19 Therapeutics

by Hyung Muk Choi, Soo Youn Moon, Hyung In Yang and Kyoung Soo Kim

Int. J. Mol. Sci. 2021, 22(4), 1737; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041737 - 09 Feb 2021

Cited by 19 | Viewed by 6471

Abstract

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has become a worldwide pandemic. Symptoms range from mild fever to cough, fatigue, severe pneumonia, acute respiratory distress syndrome (ARDS), and organ failure, with a mortality rate of 2.2%. However, there are no licensed drugs or definitive treatment strategies for patients with severe COVID-19. Only antiviral or anti-inflammatory drugs are used as symptomatic treatments based on clinician experience. Basic medical researchers are also trying to develop COVID-19 therapeutics. However, there is limited systematic information about the pathogenesis of COVID-19 symptoms that cause tissue damage or death and the mechanisms by which the virus infects and replicates in cells. Here, we introduce recent knowledge of time course changes in viral titers, delayed virus clearance, and persistent systemic inflammation in patients with severe COVID-19. Based on the concept of drug reposition, we review which antiviral or anti-inflammatory drugs can effectively treat COVID-19 patients based on progressive symptoms and the mechanisms inhibiting virus infection and replication. Full article

(This article belongs to the Special Issue COVID-19 and Molecular Studies in Biology and Chemistry)

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17 pages, 1068 KiB

Open AccessReview

Natural Killer Cell Dysfunction and Its Role in COVID-19

by Charmaine van Eeden, Lamia Khan, Mohammed S. Osman and Jan Willem Cohen Tervaert

Int. J. Mol. Sci. 2020, 21(17), 6351; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176351 - 01 Sep 2020

Cited by 117 | Viewed by 10796

Abstract

When facing an acute viral infection, our immune systems need to function with finite precision to enable the elimination of the pathogen, whilst protecting our bodies from immune-related damage. In many instances however this “perfect balance” is not achieved, factors such as ageing, cancer, autoimmunity and cardiovascular disease all skew the immune response which is then further distorted by viral infection. In SARS-CoV-2, although the vast majority of COVID-19 cases are mild, as of 24 August 2020, over 800,000 people have died, many from the severe inflammatory cytokine release resulting in extreme clinical manifestations such as acute respiratory distress syndrome (ARDS) and hemophagocytic lymphohistiocytosis (HLH). Severe complications are more common in elderly patients and patients with cardiovascular diseases. Natural killer (NK) cells play a critical role in modulating the immune response and in both of these patient groups, NK cell effector functions are blunted. Preliminary studies in COVID-19 patients with severe disease suggests a reduction in NK cell number and function, resulting in decreased clearance of infected and activated cells, and unchecked elevation of tissue-damaging inflammation markers. SARS-CoV-2 infection skews the immune response towards an overwhelmingly inflammatory phenotype. Restoration of NK cell effector functions has the potential to correct the delicate immune balance required to effectively overcome SARS-CoV-2 infection. Full article

(This article belongs to the Special Issue COVID-19 and Molecular Studies in Biology and Chemistry)

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27 pages, 1958 KiB

Open AccessReview

Obesity and COVID-19: Molecular Mechanisms Linking Both Pandemics

by Andreas Ritter, Nina-Naomi Kreis, Frank Louwen and Juping Yuan

Int. J. Mol. Sci. 2020, 21(16), 5793; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165793 - 12 Aug 2020

Cited by 91 | Viewed by 12982

Abstract

The coronavirus disease 2019 COVID-19 pandemic is rapidly spreading worldwide and is becoming a major public health crisis. Increasing evidence demonstrates a strong correlation between obesity and the COVID-19 disease. We have summarized recent studies and addressed the impact of obesity on COVID-19 in terms of hospitalization, severity, mortality, and patient outcome. We discuss the potential molecular mechanisms whereby obesity contributes to the pathogenesis of COVID-19. In addition to obesity-related deregulated immune response, chronic inflammation, endothelium imbalance, metabolic dysfunction, and its associated comorbidities, dysfunctional mesenchymal stem cells/adipose-derived mesenchymal stem cells may also play crucial roles in fueling systemic inflammation contributing to the cytokine storm and promoting pulmonary fibrosis causing lung functional failure, characteristic of severe COVID-19. Moreover, obesity may also compromise motile cilia on airway epithelial cells and impair functioning of the mucociliary escalators, reducing the clearance of severe acute respiratory syndrome coronavirus (SARS-CoV-2). Obese diseased adipose tissues overexpress the receptors and proteases for the SARS-CoV-2 entry, implicating its possible roles as virus reservoir and accelerator reinforcing violent systemic inflammation and immune response. Finally, anti-inflammatory cytokines like anti-interleukin 6 and administration of mesenchymal stromal/stem cells may serve as potential immune modulatory therapies for supportively combating COVID-19. Obesity is conversely related to the development of COVID-19 through numerous molecular mechanisms and individuals with obesity belong to the COVID-19-susceptible population requiring more protective measures. Full article

(This article belongs to the Special Issue COVID-19 and Molecular Studies in Biology and Chemistry)

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15 pages, 1894 KiB

Open AccessReview

Pulmonary Delivery of Fenretinide: A Possible Adjuvant Treatment in COVID-19

by Isabella Orienti, Giovanna Angela Gentilomi and Giovanna Farruggia

Int. J. Mol. Sci. 2020, 21(11), 3812; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113812 - 27 May 2020

Cited by 24 | Viewed by 5553

Abstract

At present, there is no vaccine or effective standard treatment for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (or coronavirus disease-19 (COVID-19)), which frequently leads to lethal pulmonary inflammatory responses. COVID-19 pathology is characterized by extreme inflammation and amplified immune response with activation of a cytokine storm. A subsequent progression to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) can take place, which is often followed by death. The causes of these strong inflammatory responses in SARS-CoV-2 infection are still unknown. As uncontrolled pulmonary inflammation is likely the main cause of death in SARS-CoV-2 infection, anti-inflammatory therapeutic interventions are particularly important. Fenretinide N-(4-hydroxyphenyl) retinamide is a bioactive molecule characterized by poly-pharmacological properties and a low toxicity profile. Fenretinide is endowed with antitumor, anti-inflammatory, antiviral, and immunomodulating properties other than efficacy in obesity/diabetic pathologies. Its anti-inflammatory and antiviral activities, in particular, could likely have utility in multimodal therapies for the treatment of ALI/ARDS in COVID-19 patients. Moreover, fenretinide administration by pulmonary delivery systems could further increase its therapeutic value by carrying high drug concentrations to the lungs and triggering a rapid onset of activity. This is particularly important in SARS-CoV-2 infection, where only a narrow time window exists for therapeutic intervention. Full article

(This article belongs to the Special Issue COVID-19 and Molecular Studies in Biology and Chemistry)

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